Molecular regulation of insulin granule biogenesis and exocytosis

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, insulin resistance and hyperinsulinemia in early disease stages but a relative insulin insufficiency in later stages. Insulin, a peptide hormone, is produced in and secreted from pancreatic β-cells following elevated blood glucose levels. Upon its release, insulin induces the removal of excessive exogenous glucose from the bloodstream primarily by stimulating glucose uptake into insulin-dependent tissues as well as promoting hepatic glycogenesis. Given the increasing prevalence of T2DM worldwide, elucidating the underlying mechanisms and identifying the various players involved in the synthesis and exocytosis of insulin from β-cells is of utmost importance. This review summarizes our current understanding of the route insulin takes through the cell after its synthesis in the endoplasmic reticulum as well as our knowledge of the highly elaborate network that controls insulin release from the β-cell. This network harbors potential targets for anti-diabetic drugs and is regulated by signaling cascades from several endocrine systems.

α-catenin isoforms are regulated by glucose and involved in regulating insulin secretion in rat clonal β-cell models

“…The proper control of glucose homeostasis relies on the appropriate levels of insulin being secreted from the β-cells in the pancreas so there has been an intense effort to understand the mechanisms by which glucose levels control insulin secretion [1,2]. Some parts of the process are understood.…”

“…The acute release of insulin upon glucose stimulation requires ATP production and subsequent closure of the ATP sensitive K + channel. The resulting membrane depolarisation leads to increased activity of voltage sensitive L-type calcium channels and the consequent influx of calcium allows t-snare/v-snare interactions that permits insulin granules to fuse with the plasma membrane [1,2].…”

In vivomonitoring of intracellular Ca2+dynamics in the pancreatic β-cells of zebrafish embryos

“…11,19 The altered [ATP/ADP] ratio in the βcell then leads to the closure of ATP-sensitive K +channels (K ATP -channels), depolarization of the membrane, and consequent opening of voltagedependent calcium channels (VDCCs). 20 The influx of Ca 2+ then triggers release of insulin from secretory granules. 21 Orthologues of all major genes (GLUT, K ATP -channels and VDCCs) involved in mammalian glucose sensing and insulin secretion are also expressed in zebrafish, and show functional similarities.…”

Characterization of the Bombyx mori homolog of islet homeostasis protein (IHoP) cDNA: BmIHoP controls insulin secretion from the β-cells

“…It is important to maintain the balance between insulin and glucagon in blood, and the involved mechanism is described in brief as follows: when blood glucose level is high, stimulation of pancreas takes place with the subsequent release of insulin from β-cells. In the case of glucagon, the hormone is released from α-cells of the pancreas, when blood glucose levels are low [5,6].…”